Memory Circuitry in MCI and Early Alzheimer's Disease: A Functional and Morphometric MRI Study of Early Detection and Longitudinal Change Rationale: Memory impairment is one of the earliest and most pronounced features of Alzheimer's Disease'(AD). Studies integrating structural and functional imaging can shed new light on brain mechanisms underlying memory deficits in AD. There is very little work to date using functional MRI to study early AD, aging, and effects on selective memory processes and no studies longitudinally integrating fMRI with volumetric and cognitive measures. Patients meeting criteria for Mild Cognitive Impairment (MCI) have a near 50 percent risk of developing AD within 4 years. The overall aims of this project are to test a model of the neuroanatomic mechanisms underlying memory impairment in MCI and mild AD using novel event-related fMRI memory activation tasks, MRI morphometry (hippocampus, entorhinal cortex [EC] and neocortical lobar regions), and to characterize longitudinal change patterns and identify baseline predictors of disease trajectory relevant to clinical outcome. Participants: will include 25 patients with mild AD (CDR 1.0; NINDS/ADRDA criteria), 66 patients with MCI (CDR 0.5), as well as 30 healthy demographically matched controls (ages 60-90, 50 percent female). Method: In Study I, during project years 1-3, we will enroll and study new patients from each of these 3 groups and perform cross- sectional analyses. In Study II, during years 2-5, we will restudy the MCI and control subjects annually to assess extent and pattern of progression using a repeated measures design. Assuming 15 percent MCI to AD conversion per year and 5 percent attrition we will have a sample of 25 converters, 30 stable MCI patients, and 25 healthy elderly controls by the end of the study for longitudinal analyses. All subjects will have detailed clinical and neuropsychological characterization including APOE and other genetic assays. Clinical status will be monitored every 6 months or less. Imaging will include a high resolution T1-weighted volumetric MRI series, T2 axial survey, flow-weighted scans, and 5 whole brain echo planar semantic, episodic and working memory activation tasks. Multivariate model testing will be employed to longitudinally characterize the pattern of relationships between fMRI hemodynamic activation, volumetric, and memory performance data including relationships with genetic/neuroprotective factors and interval clinical status. Expected Results: Our recent studies of mild AD patients show several patterns of abnormal fMRI activation in frontal and temporal neocortical sites and the hippocampal formation and EC. In new preliminary studies, fMRI memory probes have distinguished healthy elderly and MCI. The proposed longitudinal research will provide important new information on brain structure, hemodynamic activation and memory in MCI, early AD and normal aging that is directly relevant for early diagnosis, prediction of outcome, and monitoring of treatment response as new neuroprotective agents are developed.